Cyclohept[b]indolealkanoic acids, pharmaceutical compositions and use

ABSTRACT

Cyclohept[b]indolealkanoic acids and acid derivatives are disclosed. The compounds act as prostaglandin and thromboxane antagonists and are useful in treating asthma, diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea and nephrotoxicity caused by cyclosporin A and as cytoprotective agents.

CROSS-REFERENCE

This is a continuation-in-part of Ser. No. 211,800, June 27, 1988, now U.S. Pat. No. 4,906,654, which is a continuation of Ser. No. 76,096, July 21, 1987, now U.S. Pat. No. 4,775,680.

U.S. Pat. No. 4,906,654 (Gillard et al.) is incorporated herein by reference in its entirety.

DESCRIPTION OF THE INVENTION

The present invention relates to novel compounds of Formula I: ##STR1## wherein:

A is --(CR⁹ R¹⁰)_(r) R¹¹ ; R¹, R², R³, R⁴, R⁵ and R⁶ are each independently selected from:

(1) hydrogen;

(2) alkyl having 1 to 6 carbon atoms;

(3) alkenyl having 2 to 6 carbon atoms;

(4) --(CH₂)_(n) M

wherein n is 0 to 3 and M is

a) --C(O)R¹⁵ ;

b) --C(O)NR¹⁷ R¹⁷ ;

c) --CN;

d) --C(O)R¹⁶ ;

e) --C(O)CH₂ OH (hydroxymethyl ketone);

f) --CF₃ ;

g) --R¹⁴ ;

h) --tetrazole;

i) --OR¹² ;

j) --OC(O)R¹⁶ ;

k) --OC(O)NR¹⁷ R¹⁷ ;

l) --OC(O)OR¹⁸ ;

m) --SR¹³ ;

n) --S(O)R¹³ ;

o) --S(O)₂ R¹³ ;

p) --S(O)₂ NR¹⁷ R¹⁷ ;

q) --NR¹⁷ R¹⁷ ;

r) --NHC(O)R¹⁶ ;

s) --NHS(O)₂ R¹³ ;

t) --N₃ ;

u) --NO₂ ;

v) --halogen.

each R⁷ is independently H or C₁ to C₆ alkyl;

each is independently H or C₁ to C₆ alkyl;

each R⁹ is independently H or Cl to C₆ alkyl;

each R¹⁰ is independently H, OH, C₁ to C₄ alkoxy or C₁ to C₄ alkyl;

R₁₁ is --C(O)--C(O)R²⁰ ; CH₂ OH; CHO; tetrazole; --C(O)NHS(O)₂ R¹³ ; NHS(O)₂ R¹³ ;--C(O)CH₂ OH; --C(O)NR¹⁷ R¹⁷ or NHS(O)₂ OH;

each R¹² is independently H; C₁ to C₆ alkyl; benzyl; or R¹⁴ ;

each R¹³ is independently C₁ to C₆ alkyl, CF₃ or R¹⁴ ;

each R¹⁴ is independently phenyl, mono-substituted phenyl, or di substituted phenyl wherein the substituents are independently, C₁ to C₃ alkyl, C₁ to C₃ perfluoroalkyl, C₁ to C₃ alkoxy, halogen, CN, --C(O)OR¹⁵, or --CH₂ --C(O)OR¹⁵ ;

each R¹⁵ is independently H, phenyl, benzyl or C₁ to C₆ alkyl;

each R¹⁶ independently is H, R¹³ or (CH₂)_(m) C(O)OR¹⁵ ;

each R¹⁷ is independently R¹², or two R¹⁷ groups may be joined to form a 5- or 6-membered saturated ring optionally containing an oxygen atom or a second nitrogen atom, the latter being substituted by H or C₁ to C₆ alkyl;

each R¹⁸ is independently C₁ to C₆ alkyl, benzyl or phenyl;

each R¹⁹ is H, C₁ to C₆ alkyl, R¹⁴, R²¹ or R²² ;

R²⁰ is --(CH₂)_(t) --C(R⁹)₂ --(CH₂)_(t) --R²³ ;

R²¹ is --CH₂ --R¹⁴ ;

R²² is --CH₂ --CH₂ --R¹⁴

R²³ is A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, S, or O and with each ring in the heterocyclic radical being formed of 5 to 6 atoms, or B) the radical W--R²⁴ ;

R²⁴ contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;

W is 0, S or NH;

m is 0 to 4

r is 0 to 6 and

t is 0 to 3.

The novel compounds in Table 1 are a further embodiment of the present invention.

                                      TABLE 1                                      __________________________________________________________________________     Novel Cyclohept[6]indole                                                       Alkanoic Acids                                                                  ##STR2##                                       I                              Compound                                                                             R.sup.1                                                                              R.sup.2                                                                           R.sup.5  R.sup.6                                                                           R.sup.7                                                                           R.sup.8                                                                           (CR.sup.9 R.sup.10)r                                                                   R.sup.11                              __________________________________________________________________________     1 (Ex. 1)                                                                            2-F   H  4'-Cl    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            2 (Ex. 1)                                                                            2-F   H  4'-Cl    H  H  H  10-CH.sub.2                                                                            CO.sub.2 H                            3 (Ex. 2)                                                                            2-F   H  4'-Cl    H  H  H  r = 0   7-CO.sub.2 H                          4 (Ex. 3)                                                                            2-F   H  4'-Cl    H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            5     H     H  H        H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            6     H     H  4'-Cl    H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            7     2-F   4-F                                                                               4'-Cl    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            8     2-F   4-F                                                                               4'-Cl    H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            9     2-F   4-F                                                                               4'-Cl    H  H  H  r = 0   7-CO.sub.2 H                          10    2-OMe 4-F                                                                               4'-Cl    H  H  H  r = 0   6-CO.sub.2 H                          11    4-F   H  4'-Cl    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            12    4-F   H  4'-Cl    H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            13    4-SMe H  4'-Cl    H  H  H  r = 0   7-CO.sub.2 H                          14    4-Ph  H  4'-Cl    H  H  H  r = 0   6-CO.sub.2 H                          15    4-Me  H  4'-Cl    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            16    4-Me  H  4'-Cl    H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            17    4-Me  H  4'-Cl    H  H  H  r = 0   7-CO.sub.2 H                          18    4-Me  H  4'-Cl    H  H  H  r = 0   6-CO.sub.2 H                          19    2-F   4-F                                                                               2'-Cl    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            20    2-F   4-F                                                                               2'-Cl    H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            21    2-F   4-F                                                                               2'-Cl    H  H  H  r = 0   7-CO.sub.2                            22    2-F   4-F                                                                               2'-Br    H  H  H  r = 0   6-CO.sub.2 H                          23    2-F   4-F                                                                               3'-CF.sub.3                                                                             H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            24    2-F   4-F                                                                               3'-Cl    H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            25    2-F   4-F                                                                               3'-Cl    H  H  H  r = 0   7-CO.sub.2 H                          26    2-F   4-F                                                                               3'-Cl    H  H  H  r = 0   6-CO.sub.2 H                          27    2-F   4-F                                                                               2'-Cl    4'-Cl                                                                             H  H  7-CH.sub.2                                                                             CO.sub.2 H                            28    2-F   4-F                                                                               2'-Cl    4'-Cl                                                                             H  H  6-CH.sub.2                                                                             CO.sub.2 H                            29 (Ex. 7)                                                                           2-F   H  4'-S(O).sub.2 Me                                                                        H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            30    2-F   4-F                                                                               2'-Cl    4'-Cl                                                                             H  H  r = 0   6-CO.sub.2 H                          31    2-F   4-F                                                                               3' -Cl   4'-Cl                                                                             H  H  7-CH.sub.2                                                                             CO.sub.2 H                            32    2-F   4-F                                                                               3'-Cl    4'-Cl                                                                             H  H  6-CH.sub.2                                                                             CO.sub.2 H                            33    2-F   4-F                                                                               3'-Cl    4'-Cl                                                                             H  H  r = 0   7-CO.sub.2 H                          34    2-F   4-F                                                                               3'-Cl    4'-Cl                                                                             H  H  r = 0   6-CO.sub.2 H                          35    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            36 (Ex. 4)                                                                           2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            37    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  r = 0   7-CO.sub.2 H                          38    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  r = 0   6-CO.sub.2 H                          39    2-F   4-F                                                                               4'-SMe   H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            40    2-F   4-F                                                                               4'-SMe   H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            41    2-F   4-F                                                                               4'-SMe   H  H  H  r = 0   7-CO.sub.2 H                          42    2-F   4-F                                                                               4'-SMe   H  H  H  r = 0   6-CO.sub.2 H                          43    2-F   4-F                                                                               4'-S(O)Me                                                                               H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            44    2-F   4-F                                                                               4'-S(O)Me                                                                               H  H  H  6-CH.sub. 2                                                                            CO.sub.2 H                            45    2-F   4-F                                                                               4'-S(O)Me                                                                               H  H  H  r = 0   7-CO.sub.2 H                          46    2-F   4-F                                                                               4'-S(O)Me                                                                               H  H  H  r = 0   6-CO.sub.2 H                          47    2-F   4-F                                                                               4'CF.sub.3                                                                              H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            48    2-F   4-F                                                                               4'CF.sub.3                                                                              H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            49    2-F   4-F                                                                               4'-CF.sub.3                                                                             H  H  H  r = 0   7-CO.sub.2 H                          50    2-F   4-F                                                                               4'-CF.sub.3                                                                             H  H  H  r = 0   6-CO.sub.2 H                          51    2-F   4-F                                                                               4'-F     H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            52    2-F   4-F                                                                               2'-F     4'F                                                                               H  H  7-CH.sub.2                                                                             CO.sub.2 H                            53 (Ex. 5)                                                                           2-F   4-F                                                                               4'-C(O)Me                                                                               H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            54    2-F   4-F                                                                               4'-C(O)Me                                                                               H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            55 (Ex. 6)                                                                           2-F   4-F                                                                               4'-S(O).sub.2 NMe.sub.2                                                                 H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            56    2-F   4-F                                                                               3'-S(O).sub.2 NMe.sub.2                                                                 H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            57    2-F   4-F                                                                               4'-C(O)NMe.sub.2                                                                        H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            58    2-F   4-F                                                                               4'-C(O)Me                                                                               H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            59    2-F   4-F                                                                               4'-C(O)Me                                                                               H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            60    2-F   4-F                                                                               4'NHC(O)Me                                                                              H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            61    2-F   4-F                                                                               4'NHS(O).sub.2 Me                                                                       H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            62    2-F   4-F                                                                               4'NHC(O)NHMe                                                                            H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            63    2-F   4-F                                                                               4'OMe    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            64    2-F   4-F                                                                               4'OCH.sub.2 CO.sub.2 H                                                                  H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            65    2-F   4-F                                                                               4'-H     H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            66    2-F   4-F                                                                               4'-Br    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            67    2-F   4-F                                                                               4'-Cl    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            68    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  7-CH.sub.2                                                                             CH.sub.2 OH                           69    2-F   4-F                                                                               4'-Cl    H  H  H  7-CH.sub.2                                                                             CHO                                   70    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  7-CH.sub.2                                                                             CHO                                   71    2-F   4-F                                                                               4'-Cl    H  H  H  7-CH.sub.2                                                                             Tetrazol-5-yl)                        72    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  7-CH.sub.2                                                                             Tetrazol-5-yl)                        73    2-F   4-F                                                                               4' -Cl   H  H  H  6-CH.sub.2                                                                             Tetrazol-5-yl)                        74    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  6-CH.sub.2                                                                             Tetrazol-5-yl)                        75    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  r = 0   7-(Tetrazol-5-yl)                     76    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  r = 0   7-(Tetrazol-5-yl)                     77    2-F   4-F                                                                               4'-Cl    H  H  H  7-CH.sub.2                                                                             CONHS(O).sub.2 Ph                     78    2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  7-CH.sub.2                                                                             CONH.sub.2                            79    2-F   4-F                                                                               4'-Cl    H  H  H  7-CH.sub.2                                                                             NHS(O).sub.2 OH                       80    2-F   4-F                                                                               4'-C(O)Me                                                                               H  H  H  6-CHMe  CO.sub.2 H                            81    2-F   4-F                                                                               4'-NO.sub.2                                                                             H  H  H  6-CMe.sub.2                                                                            CO.sub.2 H                            82    2-F   4-F                                                                               4'-S(O).sub.2 NMe.sub.2                                                                 H  H  H  6-(CH.sub.2).sub.2                                                                     CO.sub.2 H                            83    2-F   4-F                                                                               4'-Cl    H  H  H  6-(CH.sub.2).sub.2                                                                     CO.sub.2 H                            84    2-F   4-F                                                                               4'-Cl    H  7-Me                                                                              H  7-CH.sub.2                                                                             CO.sub.2 H                            85    2-F   4-F                                                                               4'-Cl    H  6-Me                                                                              H  7-CH.sub.2                                                                             CO.sub.2 H                            86    2-F   4-F                                                                               4'-Cl    H  H  Me 7-CH.sub.2                                                                             CO.sub.2 H                            87    2-F   4-F                                                                               4'-Cl    H  H  H  8-CH.sub.2                                                                             CO.sub.2 H                            88    2-F   4-F                                                                               4'-Cl    H  H  H  9-CH.sub.2                                                                             CO.sub.2 H                            89    2-F   4-F                                                                               4'-Cl    H  H  H  cycloprop-1-yl                                                                         CO.sub.2 H                            90    2-F   4-F                                                                               4'-Cl    H  H  H  7-CH-(c-C.sub.3 H.sub.5)                                                               CO.sub.2 H                            91    2-SMe H  4'-Cl    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            92    2-S(O)Me                                                                             H  4'-Cl    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                            93    S-2(O).sub.2 Me                                                                      H  4'-Cl    H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                              (-)                                                                          94 isomer                                                                            2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                              (+)                                                                          95 isomer                                                                            2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  7-CH.sub.2                                                                             CO.sub.2 H                              (-)                                                                          96 isomer                                                                            2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                              (+)                                                                          97 isomer                                                                            2-F   4-F                                                                               4'-S(O).sub.2 Me                                                                        H  H  H  6-CH.sub.2                                                                             CO.sub.2 H                            __________________________________________________________________________

In Table I R³ ═H and R⁴ ═H. 

What is claimed is:
 1. A compound of the formula: ##STR3## wherein: A is --(CR⁹ R¹⁰)_(r) R¹¹ ;R¹, R², R³, R⁴, R⁵ and R⁶ are each independently selected from: (1) hydrogen; (2) alkyl having 1 to 6 carbon atoms; (3) alkenyl having 2 to 6 carbon atoms; (4) --(CH₂)_(n) Mwherein n is 0 to 3 and M is a) --C(O)R¹⁵ ; b) --C(O)NR¹² R¹² ; c) --CN; d) --C(O)R¹⁶ ; e) --C(O)CH₂ OH (hydroxymethyl ketone); f) --CF₃ ; g) --R¹⁴ ; h) --tetrazole; i) --OR¹² ; j) --OC(O)R¹⁶ ; k) --OC(O)NR¹² R¹² ; l) --OC(O)OR¹⁸ ; m) --SR¹³ ; n) --S(O)R¹³ ; o) --S(O)₂ R¹³ ; p) --S(O)₂ NR¹² R¹² ; q) --NR¹² R¹² ; r) --NHC(O)R¹⁶ ; s) --NHS(O)₂ R¹³ ; t) --N₃ ; u) --NO₂ ; or v) --halogen; each R⁷ is independently H or C₁ or C₆ alkyl; each R⁸ is independently H or C₁ or C₆ alkyl; each R⁹ is independently H or C₁ or C₆ alkyl; each R¹⁰ is independently H, OH, C₁ to C₄ alkoxy or C₁ to C₄ alkyl; R¹¹ is tetrazole; each R¹² is independently H, C₁ to C₆ alkyl, benzyl, or R¹⁴ ; each R¹³ is independently C₁ to C₆ alkyl, CF₃, or R¹⁴ ; each R¹⁴ is independently phenyl, mono-substituted phenyl, or di-substituted phenyl wherein the substituents are independently C₁ to C₃ alkyl, C₁ to C₃ perfluoroalkyl, C₁ to C₃ alkoxy, halogen, CN, --C(O)OR¹⁵, or --CH₂ --C(O)OR¹⁵ ; each R¹⁵ is independently H, phenyl, benzyl, or C₁ to C₆ alkyl; each R¹⁶ independently is H, R¹³, or (CH₂)_(m) C(O)OR¹⁵ ; each R¹⁸ is independently C₁ to C₆ alkyl, benzyl, or phenyl;m is 0 to 4; r is 0 to 6; and t is 0 to
 3. 2. A compound of claim 1, wherein:R¹, R², R³, R⁴, R⁵ and R⁶ are each independently selected from: (1) hydrogen; (2) alkyl having 1 to 6 carbon atoms; (3) alkenyl having 2 to 6 carbon atoms; (4) --(CH₂)_(n) M, wherein n is 0 or 1; and r is 1 to
 6. 3. A compound of to claim 2, wherein:A is attached to the 6- or 7-position; n is 0; and r is 1 or
 2. 4. A compound of claim 3, wherein:A is attached to the 6- or 7-position; R¹, R², R³ and R⁴ are each independently selected from: (1) hydrogen; (2) alkyl having 1 to 6 carbon atoms; (3) M, wherein M isa) --C(O)OR¹⁵ ; b) --C(O)NR¹² R¹² ; c) --CN; d) --C(O)R¹⁶ ; f) --CF₃ ; h) --tetrazole; i) --OR¹² ; j) --OC(O)R¹⁶ ; m) --SR¹³ ; n) --S(O)R¹³ ; o) --S(O)₂ R¹³ ; p) --S(O)₂ NR¹² R¹² ; t) --N₃ ; or v) --halogen; R⁵ and R⁶ are independently selected from: (1) hydrogen; (2) alkyl having 1 to 6 carbon atoms; (3) M, wherein M isa) --C(O)OR¹⁵ ; b) --C(O)NR¹² R¹² ; c) --CN; d) --C(O)R¹⁶ ; f) --CF₃ ; h) --tetrazole; n) --S(O)R¹³ ; o) --S(O)₂ R¹³ ; p) --S(O)₂ NR¹² R¹² ; t) --N₃ ; u) --NO₂ ; or v) --halogen; each R¹⁰ is independently H or C₁ to C₄ alkyl; and r is
 1. 5. A compound of claim 1 of the formula:

    ______________________________________                                          ##STR4##                                                                      Compound  R.sup.5     (CR.sup.9 R.sup.10).sub.r                                                              R.sup.11                                         ______________________________________                                         71        4'-Cl       7-CH.sub.2                                                                             Tetrazol-5-yl                                    72        4'-S(O).sub.2 Me                                                                           7-CH.sub.2                                                                             Tetrazol-5-yl                                    73        4'-Cl       6-CH.sub.2                                                                             Tetrazol-5-yl                                    74        4'-S(O).sub.2 Me                                                                           6-CH.sub.2                                                                             Tetrazol-5-yl                                    75        4'-S(O).sub.2 Me                                                                           r = 0   7-(Tetrazol-5-yl)                                76        4'-S(O).sub.2 Me                                                                           r = 0   7-(Tetrazol-5-yl)                                ______________________________________                                    


6. A compound of claim 1, which is a pure optical isomer.
 7. A compound of claim 6, which is the (+)-isomer.
 8. A compound of claim 6, which is the (-)-isomer.
 9. A method of inhibiting leukotriene synthesis in a mammal, which comprises administering to a mammal an effective amount of a compound of claim
 1. 10. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier. 